Our laboratory is focused on understanding the role of the tumor microenvironment in cancer progression. Despite many great strides in cancer research, metastasis, the most devastating phase of tumor progression, remains poorly defined. Traditionally, theories of metastasis describe a multi-step process involving tumor cells accumulation of multiple genetic alterations promoting motility, growth and an invasive phenotype. However, genetic insights now suggest that metastatic propensity exists much earlier in tumor growth than was previously appreciated. Moreover, identification of genetic profiles intrinsic to the tumor cell that correlate with aggressive metastatic disease does not, in itself, reveal all details of the molecular and cellular events by which invasion and metastasis occurs, or of how it is orchestrated. Our work has caused a paradigm shift in understanding the stepwise events in metastatic disease. We focus on metastasis as an active process involving communication between the primary tumor and the entire host representing a systemic phenomenon with localized chemokine gradients being established in response to mobilization of bone marrow-derived cells to tissue-specific sites. Primary tumor growth and metastatic progression are preferentially dependent on the microenvironment in which these tumor cells reside. It has also long been recognized that the preferential colonization of cancer to specific tissues such as lymph nodes, bone, lung and brain are in part determined by the nature of the microenvironment within these distant organs as initially proposed by Stephen Paget. More recently, details of the early changes occurring within distant tissue stroma, involving the creation of a supportive microenvironment permissive for metastatic growth, have been recognized. The host genetic makeup within cells such as endothelial cells, hematopoietic cells, fibroblasts and immune cells all contribute to the growth and migration of tumors cells. Understanding the interaction between cancer cells and their supportive stromal components at sites of future metastasis, and the molecular cross-talk that is conducive to establishment of secondary tumor growth is now paramount. This work may reveal targets for novel therapeutic and prognostic strategies to treat and prevent metastatic cancer. We plan to study the specific cell populations including resident cells and recruited cell populations that are present in distant host sites of metastasis early in the metastatic cascade prior to full blown vascularized metastatic lesions and through development to established vascularized metastases. Further we will characterize the molecular and cellular changes within the pre-metastatic niche sites. We aim to discover novel expression patterns by gene expression profiling of murine and human metastatic tissue. We can then compare different metastatic tissue sites as well as the bone marrow changes that occur in murine models of metastasis as well as patients with malignancy. These studies will also help improve our understanding of adult stem and progenitor cells and their response to cancer progression. Analysis of the pathological impact on adult tissue specific stem cells may help to devise novel strategies for regenerative medicine as well as cancer therapies. It is our goal to use these unique approaches to improve effective therapies for patients with cancer progression.